The long range goals of the laboratory are to define in detail the antigenic requirements for induction, the specificity for H-2 and virus-associated determinants, and the genetic control of both the induction and the specificity of cytotoxic T lymphocyte (CTL) responses to weakly immunogenic antigens on syngeneic tumors induced by AKR/Gross MuLV. In addition we will investigate one possible mechanism of tumor escape from immune surveilance. Namely, some MuLV-induced tumors may be resistant to the ability of gamma interferon to augment cell surface H-2 expression. Although study of the high-leukemic AKR strain is the ultimate goal, this strain represents a very complex situation. Therefore, initial studies have dealt with the low-leukemic C57BL/6 (B6) strain which is genetically resistant to Gross virus-induced leukemia, but for which teh syngeneic tumor cell prototype for the definition of the Gross cell surface antigen (GCSA) exists. These studies resulted in the description of a scheme for raising H-2Kb restricted cytotoxic T cells specific for that subclass of endogenous AKR/Gross virus-induced leukemias which display GCSA. The present proposal would first further define this system so that a firm experimental basis would be obtained for the investigation of other strains of mice. Then, various F1, congenic, H-2 recombinant inbred and H-2Kb mutant mice, some of whose genotypes reflect differing contributions by donor strains of mice of high-leukemic phenotype, will be employed. Such an approach will extend our previous experiments which have shown the influence of both H-2 encoded genes and genes controlling viral antigen expression on antiviral CRL responsiveness. These studies thus ultimately serve as an approach towards the in-depth study of CTl responses in high-leukemic mice. Thus, a complicated, perhaps specifically immunodepressed system such as the AKR mouse can be systematically dissected by gradually building from a known positive system. With knowledge of the effects of individual genetic loci and viral influences, the AKR mouse can better be approached to determine if it is indeed nonresponsive to its spontaneously arising leukemias, and if so, how the system can be manipulated to promote an effective immune response. Definition of strageties to augment cell mediated responses to these weakly immunogenic antigens may have broad applicability to immune intervention to tumors in higher species.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA036860-06
Application #
3174448
Study Section
Experimental Immunology Study Section (EI)
Project Start
1983-09-01
Project End
1991-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
6
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Dartmouth College
Department
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
03755
Green, W R (1999) Cytotoxic T lymphocytes to endogenous mouse retroviruses and mechanisms of retroviral escape. Immunol Rev 168:271-86
Barth Jr, R J; Coppola, M A; Green, W R (1996) In vivo effects of locally secreted IL-10 on the murine antitumor immune response. Ann Surg Oncol 3:381-6
Coppola, M A; Lam, T M; Strawbridge, R R et al. (1995) Recognition of endogenous ecotropic murine leukaemia viruses by anti-AKR/Gross virus cytotoxic T lymphocytes (CTL): epitope variation in a CTL-resistant virus. J Gen Virol 76 ( Pt 3):635-41
Buhlmann, J E; Foy, T M; Aruffo, A et al. (1995) In the absence of a CD40 signal, B cells are tolerogenic. Immunity 2:645-53
Coppola, M A; Green, W R (1994) Cytotoxic T lymphocyte responses to the envelope proteins of endogenous ecotropic and mink cytopathic focus-forming murine leukemia viruses in H-2b mice. Virology 202:500-5
White, H D; Roeder, D A; Green, W R (1994) An immunodominant Kb-restricted peptide from the p15E transmembrane protein of endogenous ecotropic murine leukemia virus (MuLV) AKR623 that restores susceptibility of a tumor line to anti-AKR/Gross MuLV cytotoxic T lymphocytes. J Virol 68:897-904
White, H D; Roeder, D A; Lam, T et al. (1994) Major and minor Kb-restricted epitopes encoded by the endogenous ecotropic murine leukemia virus AKR623 that are recognized by anti-AKR/Gross MuLV CTL. Viral Immunol 7:51-9
Durie, F H; Aruffo, A; Ledbetter, J et al. (1994) Antibody to the ligand of CD40, gp39, blocks the occurrence of the acute and chronic forms of graft-vs-host disease. J Clin Invest 94:1333-8
White, H D; Green, W R; Gine, N R (1993) Molecular cloning of infectious ecotropic murine leukemia virus AK7 from an emv-14-positive AKXL-5 mouse and the resistance of AK7 to recognition by cytotoxic T lymphocytes. J Virol 67:5045-50
Schwarz, D A; Buhlmann, J E; Kuhne, M R et al. (1993) Novel regulation of an MHC class I gene response to interferon-gamma. Cell Immunol 150:90-100

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